This Program Project is an integrated effort focused on the development and use of unique animal tumor models represented by Xiphophorus interspecies hybrids, and is designed to investigate the molecular and genetic basis of tumor susceptibility. The Program is constituted of three Research Projects and two Cores. Project 1 will intensively investigate the role of ultraviolet (UV) radiation in melanoma formation, determining UV action spectra for melanomagenesis and for the induction and repair of UV-induced DNA damage in Xiphophorus tissues, tumors and cell lines. A particular focus will be the roles of a dominant oncogene (Xmrk) and tumor suppressor genes (CDKN2K, p53) in melanoma. Project 2 will develop a new and promising Xiphophorus model for neuroblastoma, and will use the alkylating chemical carcinogen N-methyl-N-nitrososurea (MNU) for melanoma, fibrosarcoma, and neuroblastoma induction in Xiphophorus hybrids. Experiments conducted in Projects 1 and 2 will allow comparison of UV- and MNU-induced carcinogenesis in genetically diverse melanoma models. DNA damaged induced by alkylating carcinogens and DNA repair will be correlated to endpoints such as toxicity and tumorigenesis, using specific radioimmunoassays and biochemical approaches to investigate repair mechanisms. Project 3 is concerned with expansion of the Xiphophorus gene map, providing markers useful for locating potential tumor susceptibility loci in all 24 Linkage Groups (LGs) for each of the established and new Xiphosphous hybrid tumor models to be developed in these studies. In all Research Projects, genetic linkage analysis, coordinated through Project 3, will be used to identify and locate in the Xiphophorus gene map any loci associated with tumor susceptibility. Core A will provide administrative and research support to the Research Projects, including biostatistics and histopathology support. In addition, fiscal administration, organization of internal research group interactions will be implemented by Core A. Core B will supervise and maintain all fish stocks and strains, and perform hybridizations, production of tumor susceptible backcross hybrids, UV and MNU treatments, outgrowth, and dissections to provide materials for analysis to the individual projects. These integrate goals offer the prospect of addressing fundamental, broadly relevant scientific questions concerning the molecular and genetic basis of genetic susceptibility to tumorigenesis.